Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase having α and β isoforms that are each encoded by distinct genes (Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); and Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)). GSK-3 has been implicated in various diseases including diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy (see, e.g., WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117). These diseases may be caused by, or may result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role.
GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These include glycogen synthase, which is the rate-limiting enzyme required for glycogen synthesis, the microtubule-associated protein Tau, the gene transcription factor β-catenin, the translation initiation factor e1F-2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-myc, c-myb, CREB, and CEPB α. These diverse targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.
Small molecule inhibitors of GSK-3 have recently been reported (WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)), however, there is a continued need to find more effective therapeutic agents to treat GSK-3 mediated diseases.